tbuckley/cabot-search huggingface dataset:
Abstract 3158: Defining the mechanisms that lead to mutational heterogeneity in the normal respiratory epithelium
Authors: Kate H. Gowers, Sarah E. Clarke, Ayu Hutami Syaraf, Kenichi Yoshida, Moritz J. Przybilla, Hugh Selway, Adam Pennycuick, Peter J. Campbell, Sam M. Janes
Journal: Cancer Research (2022)

Abstract It is well established that tobacco smoking causes lung cancer and this is thought to be the result of a progressive accumulation of genomic mutations induced by tobacco smoke exposure; however, until recently a detailed understanding of the effects of smoke exposure on the genomes of cells in the normal bronchial epithelium was lacking. To address this, we defined the genomic architecture of normal airway basal cells in children and non-smoking, smoking and ex-smoking adults. We discovered two populations of basal cells in individuals with a smoking history: those with high mutational burden, driver gene mutations and tobacco-associated mutational signatures, and those with low mutational burden, similar to basal cells from never smokers and with an absence of mutational signatures associated with tobacco exposure. These cells expand preferentially in ex-smokers, accounting for 20-40% of basal cells compared with 2-5% in current smokers. We hypothesise that these cells are cancer-protective and their expansion reduces the risk of lung cancer development after smoking cessation. Understanding the functional differences between high- and low-mutant airway basal cells and the mechanisms by which some cells resist the accumulation of smoking-induced mutations will be crucial to understanding the earliest stages of lung carcinogenesis. To address this, we performed RNAseq on a subset of whole-genome sequenced airway basal cells. Preliminary data show that expression of markers of stemness is significantly different between high- and low-mutant basal cells. In addition, initial analysis shows that pathways such as carcinogen metabolism and MHC class I antigen presentation are higher in high-mutant basal cells. Further analysis in more patients is ongoing. To complement these data, we expanded whole-genome sequenced basal cell clones in culture and performed a range of assays to assess their progenitor and differentiation capacity. We assessed proliferation, colony-forming efficiency, longevity and differentiation and found no apparent differences between low- and high-mutant basal cells. Initial analysis suggests that carcinogen metabolism and MHC class I antigen presentation may be key pathways in establishing heterogeneity in mutational burden and clonal dynamics in the normal airway epithelium. Additional assays and analysis are ongoing and will be the focus of future research. Citation Format: Kate H. Gowers, Sarah E. Clarke, Ayu Hutami Syaraf, Kenichi Yoshida, Moritz J. Przybilla, Hugh Selway, Adam Pennycuick, Peter J. Campbell, Sam M. Janes. Defining the mechanisms that lead to mutational heterogeneity in the normal respiratory epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3158.
Abstract 6101: K6-K14 keratin fusion variant (K6-K14/V7) in OSCC cells promotes tumor microenvironment remodeling through activating inflammatory CAFs
Authors: Brian Yu-Ting Kuo, Yen-Ting Lin, Senthilkumar Ravichandran, Jim Jinn-Chyuan Sheu
Journal: Cancer Research (2022)

Abstract Keratin intermediate filament is one major cytoskeleton architecture in epithelial cells, providing necessary mechanical support to maintain cell shape and tissue integrity. In a previous study, we discovered the existence of a novel K6-K14 keratin fusion variant (K6-K14/V7) in oral squamous cell carcinoma (OSCC) cells which can promote cancer stemness and aggressiveness. However, the underlying mechanism remains to be elucidated. Here, we report that overexpression of K6-K14/V7 in OSCC cells can influence the mechanical properties of the cells, leading to cell protrusion and enhanced extracellular vesicle (EV) secretion. Consequently, the expression levels of inflammatory cytokines (e.g. IL-6, TGF-[[Unsupported Character - Symbol Font β]]) in the culture medium can be also increased. Normal oral fibroblast cells co-cultured with K6-K14/V7-expressing OSCC cells can be converted into a pro-inflammatory type of cancer-associated fibroblasts (iCAFs). Those findings suggest the ability of K6-K14/V7-expressing OSCC cells in remodeling tumor microenvironment. In this study, we will discuss how K6-K14/V7-expressing OSCC cells educate iCAFs to promote cancer cell migration and invasion via intercellular communication by EVs. The key signaling cascades and the associated regulatory networks will be also discussed. Our study, therefore, uncovers the pro-tumorigenic functionality of K6-K14/V7 by creating an inflammatory tumor microenvironment. Citation Format: Brian Yu-Ting Kuo, Yen-Ting Lin, Senthilkumar Ravichandran, Jim Jinn-Chyuan Sheu. K6-K14 keratin fusion variant (K6-K14/V7) in OSCC cells promotes tumor microenvironment remodeling through activating inflammatory CAFs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6101.
Abstract 5702: Cancer-specific glycosylation regulated by epigenomic alteration in renal cell carcinoma
Authors: Yoshiko Kitazume, Eri Arai, Atsushi Matsuda, Kentaro Ohara, Akiko Miyagi Maeshima, Teruhiko Yoshida, Atsushi Kuno, Yae Kanai
Journal: Cancer Research (2022)

Abstract Background and Aims: Cancer-specific glycosylation plays an important role in the development and progression of cancer. Epigenetics may contribute to forming cancer-specific glycosylation by regulating the expression of glycogenes. Although comprehensive analysis of epigenetics is routinely performed, comprehensive glycan analysis, especially using human clinical samples, has been limited due to technical underdevelopment. Our aims are to understand the significance of glycosylation and its epigenetic regulation on renal carcinogenesis and to identify cancer-specific glycosylation as a potential diagnostic marker and a novel therapeutic target. Materials and Methods: Comprehensive glycomics and methylome analysis were performed by lectin microarray and Infinium HumanMethylation450 BeadChip on 50 non-cancerous renal cortex tissue (N) and 50 clear cell renal cell carcinoma (RCC) (T) microdissected from formalin-fixed and paraffin-embedded tissue samples. Results: Compared to N samples, T samples showed higher fluorescence intensity for lectins recognizing mannose-type glycans, and lower intensity for lectins recognizing sialyl and fucosyl groups. In RCC, the metabolism of N-glycans may remain in an immature state. By hierarchical clustering using lectin microarray data, T samples were divided into Clusters A and B with significant differences in patients’ outcome. Increased high-mannose type N-glycan and core fucosylation and decreased sialylation were observed in T samples of Cluster A. According to these results, glycosylation profiles showed heterogeneity associated with patients’ outcome among RCCs, and immature N-glycan may be specific in some RCCs. Methylome analysis suggests that specific glycosylation profiles of RCCs may be induced by DNA methylation alteration on glycogenes. Association between DNA methylation and mRNA expression was confirmed on some glycogenes using real-time reverse transcription PCR. As a result of examining whether the signal intensity pattern of each lectin reflects the prognosis of clear cell RCC, we could identify the lectins that reflect the RCCs prognosis. Conclusion: In RCC, the metabolism of N-glycans may remain in an immature state. The glycan profiles show heterogeneity among individual RCCs, and some of the specific glycan profiles may be associated with patients’ outcome. Cancer-specific glycan profiles may be regulated by epigenetic alteration of glycogenes. Citation Format: Yoshiko Kitazume, Eri Arai, Atsushi Matsuda, Kentaro Ohara, Akiko Miyagi Maeshima, Teruhiko Yoshida, Atsushi Kuno, Yae Kanai. Cancer-specific glycosylation regulated by epigenomic alteration in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5702.
JAMA Cardiology
Authors: Patrick O'gara, Marc Sabatine, Clyde Boston, Ann Yancy, Michael Pencina, Carolina North, Robert Harrington, Adrian Hernandez, Mhs Durham, North Carolina, Ajay Kirtane, New York, Roxana Mehran, Pradeep Natarajan, Kristen Boston, Seattle Patton, Washington Udelson, Sadiya Khan, Gregg Fonarow, Los Angeles, Sharlene Day, Laine Thomas, Akhil Narang, Julia Getts, Eugene Braunwald, Judith Hochman, Donald Lloyd-Jones, Scm Chicago, Michael Parmacek, Daniel Simon, Sidney Smith, Chapel Hill, Carolina Douglas, E Vaughan, Myron Weisfeldt, Maryland Douglas, P Zipes, Paul Armstrong, Shinya Goto, Peter Liu, Renato Lopes, Carolina Prabhakaran, Hugh Watkins, Harvey White, Habib Yacoub, Frs London, Phil Fontanarosa, Annette Flanagin, Robert Golub, Michael Berkwits, Brenda Gregoline, Tracy Frey, Iris Lo, Kevin Brown, Bernadette Hromin, Erin Keenan, Rebecca Langley, Kris Simmons, Connie Manno, Sara Billings, Doug Brandt, Timothy Gray, Peter Olson, Juliet Orellana, Paul Ruich, Kirby Snell, Judith Ahlers, Stephanie Beckmeyer, Dawn Bielawski, Jane Calayag, Jan Clavey, Mary Coerver-Connolly, Amy Eutsey, Paul Jaworski, Ruth Kaufman, Laura King, Julia Kurtz, Martha Lentz, Donna Lysak, Jenny Mackay, Charon Pierson, Lori Ryan, Thressa Smith, Annette Theuring, Donna Thordsen, Christine Tilles, Suzanne Walker, Cara Wallace, Becki Weiss, Christina West, Caroline Woods, Larry Bryant, Jacob Kendall-Taylor, Monica Mungle, Lenette Gardner-Gullens, Fanny Brown, Anna Bukowski, Lee Calibeo, Tosca Hall, Erin Kato, Rachell Lozano, Kenneth Otani, Caroline Sietmann, Angelia Waltower, Jesse Mcquarters, Elena Guobyte, Emily Ling, Daniel Morrow, Shelly Steff, Deanna Bellandi, Jim Michalski, Eman Aly, Reuben Rios, Mary Ferkaluk, Jonathan Laxamana, Sidra Bonner, Heather Hsu, Andrew Ibrahim, Karen Bucher, Andy Rekito, Nick Reback, Lohitha Kethu, Marla Erson, Joseph Thornton, Thomas Easley, Brian Shields, Karen Adams-Taylor, Paul Gee, Monica Smith, Julie Burton, Ronna Hewitt, Mary Sieck, Geneine Someren, Jamaal Vargas, Content Systems, Mike Bujewski, Nathan Mitre, Digital Production, Regina Brownlee, Amanda Camino, Brenda Chandler-Grayer, Emily Dunn, Amy Evers, Maleeka Holden, Teri Hutchison, Dan Knowles, Joshua Lampinen, Natalie Marsh, Patricia Panek, Marla Seidell, La Son, Diggs Sledge, Julian Graphics, Joe Amft, Jonathan Chala, James Collver, Maria Duda, Fred Furtner, Carolyn Hall, Maria Kowalkowski, Joy Farrell, Maria Giannini, Sasha Grossman, Kate Lander, Judith Literskis, Teresa Omiotek, Michael Ryder, James Madara, Robert Bonow
Journal: JAMA Cardiology (2022)

science, is a leading editorial priority.
Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium
Authors: Hilary A. Robbins, Aida Ferreiro-Iglesias, Tim Waterboer, Nicole Brenner, Mari Nygard, Noemi Bender, Lea Schroeder, Allan Hildesheim, Michael Pawlita, Gypsyamber D'Souza, Kala Visvanathan, Hilde Langseth, Nicolas F. Schlecht, Lesley F. Tinker, Ilir Agalliu, Sylvia Wassertheil-Smoller, Eivind Ness-Jensen, Kristian Hveem, Sara Grioni, Rudolf Kaaks, Maria-Jose Sánchez, Elisabete Weiderpass, Graham G. Giles, Roger L. Milne, Qiuyin Cai, William J. Blot, Wei Zheng, Stephanie J. Weinstein, Demetrius Albanes, Wen-Yi Huang, Neal D. Freedman, Aimée R. Kreimer, Mattias Johansson, Paul Brennan
Journal: Journal of Clinical Oncology (2022)

PURPOSE Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown. METHODS We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality. RESULTS The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status. CONCLUSION We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.
Abstract 4023: Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma
Authors: Amanda Linke, Rachel Burge, Aaron Hobbs
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third most deadly human cancer with a dismal five-year survival rate of 10%. KRAS is mutated in over 95% of PDAC tumors and is a key driver of PDAC tumorigenesis. Mutant KRAS is constitutively active and drives proliferation through the upregulation of numerous signaling and metabolic pathways to support tumor proliferation. Despite the promise of targeted inhibitors of the RAF-MEK-ERK MAPK signaling pathway, arguably the most critical RAS-mediated proliferative signaling pathway, clinical trials targeting oncogenic MEK/ERK signaling as a single-agent therapy have been unsuccessful. The PDAC tumor microenvironment has been shown to be depleted of glutamine and free amino acids, suggesting that PDAC relies heavily on nontraditional metabolic processes for proliferation such as macropinocytosis, the nonselective uptake of proteins and molecules from extracellular spaces, and autophagy, a mode of cellular recycling. Macropinocytosis has been shown to be elevated in PDAC cell lines and human tumors. Despite recent findings describing the limited nutrient availability in the tumor microenvironment, cell culture studies supporting the use of MEK/ERK inhibitors are predominately performed in a high glutamine medium. By utilizing a minimal glutamine medium supplemented with bovine serum albumin, a large protein that is absorbed via macropinocytosis, we show that this growth medium drives resistance to MEK MAPK inhibition. To evaluate whether PDAC cells proliferating in a low glutamine medium can be sensitized to MEK inhibition, we have performed a CRISPR/Cas9 loss-of-function screen targeting the druggable genome to determine effective therapeutic combinations under these conditions. To follow up on our in vitro screen, we will evaluate the therapeutic efficacy of our findings with 2D and 3D PDAC proliferation assays. These studies will describe novel treatment strategies for PDAC patients with elevated macropinocytosis. Citation Format: Amanda Linke, Rachel Burge, Aaron Hobbs. Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4023.
Abstract 3444: Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma
Authors: Sanjay Pandey, Claudia G. Chavez, Indranil Basu, Andy Minn, Chandan Guha
Journal: Cancer Research (2022)

Abstract Resistance to immune checkpoint therapy develops in a subset of patients after initial response. Therefore, we hypothesized that defective antigen presentation contributes to immune resistance, and a sequential therapy comprising of ablative radiation therapy (RT) and agonist αCD40 antibody can reprogram the tumor-infiltrating myeloid and dendritic cells for effective in-situ tumor antigen presentation and activation of T cells. Palpable B16-F10-Res499 tumors in C57BL/6 mice, resistant to the systemic effects of RT and αCTLA-4 blockade, were treated with 3 fractions of 20Gy (RT) followed by agonist αCD40 antibody (3x100μg). Tumor growth, survival, and anti-tumoral immune memory after rechallenge was monitored. Mice were sacrificed on Day 16 post-RT, and immune cells from irradiated tumors and draining lymph nodes (DLN) were analyzed using flow cytometry. There was complete tumor regression and enhanced anti-tumoral immune memory in RT+αCD40-treated animals. In a dual tumor model, combination therapy significantly delayed abscopal tumor growth by 64% on D30 (p&amp;lt;0.0001). When compared to unirradiated or tumors treated with RT alone, there was a significant increase in cell surface expression of co-stimulatory molecules (CD80, CD86, CD40 and 4-1BBL) and TNF-α, and iNOS in the CD103+ DCs and myeloid cells (p&amp;lt;0.05) indicating a reprogramming of antigen presentation and co-stimulatory function in MDSCs. There was an increase in CD8+ T cells with reduced CD4/CD8 ratio (p&amp;lt;0.01) in abscopal tumors and DLN in the RT+αCD40 group. Combination treatment enhanced the frequency of proliferating Ki67+ (p&amp;lt;0.001) and IFNγ+ (p&amp;lt;0.01) CD8 T cells and an increase in the Ki67+ high GRZ+ (granzyme secreting) population in the pool of early exhausted cells (PD1intEOMESlow). Interestingly CD8 depletion by anti-CD8 only partially reversed the effect of the combination group. Furthermore, αCD40 showed an increase in the CD11b+Ly6C population in the tumors. Also, Ly6C depletion completely reversed the effect of the IR+anti-CD40 treatment. Conclusion: Combination of ablative RT, followed by αCD40 therapy, overcame immune resistance in murine melanoma by enhancing systemic anti-tumoral immunity, abscopal effects, survival, and anti-tumoral immune memory. The immunomodulatory effects of αCD40 are dependent upon Ly6C+ cells and partially on CD8+ T cells. Citation Format: Sanjay Pandey, Claudia G. Chavez, Indranil Basu, Andy Minn, Chandan Guha. Administration of anti-CD40 enhances local and systemic antitumor efficacy of radiotherapy in allograft tumor model of a check-point blockade resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3444.
Abstract 2596: Impact of novel Ku-DNA binding inhibitors on the DNA DSBs-induced DNA damage response
Authors: Pamela L. Mendoza-Munoz, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Joseph R. Dynlacht, Joy E. Garrett, John J. Turchi
Journal: Cancer Research (2022)

Abstract The DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) double-strand break (DSB) repair pathway and the DNA damage response (DDR). Consequently, blocking DNA-PK kinase activity is a novel anti-cancer therapeutic strategy in combination with ionizing radiation (IR). Towards developing a new class of DNA-PK inhibitors, our laboratory has exploited the mechanism of DNA-PK activation which requires binding to DNA termini via the Ku 70/80 heterodimer. We have previously reported the development of Ku-DNA binding inhibitors (Ku-DBi’s) that act via this novel mechanism of action to inhibit DNA-PK catalytic kinase activity. Ku-DBi’s display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity and sensitize non-small cell lung cancer (NSCLC) cells to DSB generating chemotherapeutics bleomycin and etoposide. In this study, we demonstrate that pre-incubation of our novel Ku-DBi’s can potentiate the cellular effects of bleomycin and IR and also induce p53 phosphorylation through the activation of the ATM pathway, which is concomitant with a decrease in DNA-PKcs autophosphorylation events at the S2056 (pS2056) cluster. Using a combination of Western blot and immunofluorescence assays in the NSCLC NCI-H460 and A549 cell lines, Ku-DBi’s treatment in combination with DNA DSBs-inducing agents such as bleomycin and IR, showed a significant reduction of autophosphorylation events of DNA-PKcs at the S2056 cluster compared to DNA DSBs-inducing agent alone. In addition, analysis of phospho-ATM and phospho-p53 protein levels in these NSCLC cell lines, suggested activation of the ATM pathway as a function of Ku-DBi’s treatment followed by bleomycin, evidenced by an increase of phosphorylation of ATM at Ser1981, and a modest increase of p53 phosphorylation at Ser15. Our findings demonstrate that Ku-DBi’s block DNA-DSB dependent DNA-PKcs autophosphorylation, resulting in potentiating cellular sensitivity to bleomycin and IR, and a likely effect on the ATM-dependent signaling pathway. These data are consistent with Ku-DBi’s possessing a novel mechanism of action that abrogates autophosphorylation of DNA-PKcs to impact DSB repair and potentially DDR signaling, becoming in a promising approach as part of an anticancer therapeutic strategy in combination with DNA DSBs-inducing agents. Citation Format: Pamela L. Mendoza-Munoz, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Joseph R. Dynlacht, Joy E. Garrett, John J. Turchi. Impact of novel Ku-DNA binding inhibitors on the DNA DSBs-induced DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2596.